The long term goals of this program project are an understanding of an inflammatory demyelinating disease of the central nervous system (CNS) induced and associated with viral infection. To this end, the projects in this program are analyzing the mechanisms of a defined model of CNS demyelination induced by the neurotropic JHM strain (MHV-4) of mouse hepatitis virus (JHMV). This model provides a means to understand the interactions between a pathogen and host that result in either an acute or persistent CNS infection. The persistent or chronic form of this infection is associated with ongoing primary demyelination a pathology similar to that seen in multiple sclerosis. Virus can not be isolated from chronically infected animals and the demyelinating lesions eventually begin to resemble a chronic plaque in multiple sclerosis. Multiple sclerosis raises many questions related to both the role of virus in induction and the immune response in the pathogenesis of demyelination. The JHMV model provides a mechanism to address fundamental questions of viral persistence, neurotropism, and immune responses, both as protective mechanisms and as inducers of demyelination. The core principle investigators have been stable and are actively collaborating. The program consists of four projects. These projects include a molecular analysis of CNS tropism via analysis of the viral receptor and mechanism of entry, an analysis of the effective mechanisms used to control virus replication in specific CNS cell types, the basis for T cell migration, the acquisition of effector phenotypes with the CNS parenchyma, and the molecular basis of viral persistence leading to chronic demyelination.